This invention relates to process technology suitable for producing on an industrial scale 4-fluorobenzaldehyde, a useful raw material for producing certain pharmaceutical products.
Over the years a number of laboratory synthesis procedures have been published in the technical and patent literature for preparation of various aromatic aldehydes from benzene or substituted benzenes using carbon monoxide and a Lewis acid such as aluminum chloride. While some of these procedures can be conducted on a laboratory scale, they are often unsuitable for use on an industrial scale for various reasons such as low yields or use of impractical or uneconomical reaction conditions. Moreover, such laboratory procedures usually fail to take into consideration problems which can arise because of by-products which often are formed in the course of the methods used.
An objective of this invention is to provide process technology suitable for producing 4-fluorobenzaldehyde on an industrial scale.
This invention provides process technology which is suitable for producing 4-fluorobenzaldehyde on a commercial scale. The process technology of this invention not only makes possible the production of 4-fluorobenzaldehyde in good yields under practical reaction conditions, but in addition avoids or at least minimizes potential corrosion problems that could otherwise occur in actual practice in industrial plant facilities due to the formation of relatively small amounts of halobis(fluorophenyl)methane as a by-product of the reaction. In addition, this invention eliminates or at least minimizes the extent to which the final reaction product discolors on exposure to light.
Pursuant to one embodiment of this invention, 4-fluorobenzaldehyde is produced by a process which comprises:
A) heating in a reactor a mixture of fluorobenzene and a strong Lewis acid, most preferably aluminum chloride, in the presence of a hydrogen halide and in a carbon monoxide atmosphere at a temperature in the range of about 45 to about 100xc2x0 C. and at a total pressure in the range of about 150 psig to the maximum pressure rating of the reactor being used to form a reaction mass comprising at least (i) a complex of 4-fluorobenzaldehyde with the Lewis acid used, and (ii) halobis(fluorophenyl)methane by-product;
B) breaking such complex by quenching the reaction mass with a Lewis acid-solvating liquid such as water to liberate 4-fluorobenzaldehyde; and
C) converting halobis(fluorophenyl)methane into di(fluorophenyl)methanol, to thereby eliminate or reduce potential corrosion problems and development of color in the 4-fluorobenzaldehyde on exposure to light.
Accordingly, the process makes it possible to either (i) recover 4-fluorobenzaldehyde or (ii) use the 4-fluorobenzaldehyde as a reactant without isolation without encountering significant corrosion or color formation in the product.
Of the hydrogen halides that can be used in the above process (HCl, HBr, HI, and/or HF), HCl and/or HBr are preferred, with HCl being most preferred. Such hydrogen halides should be anhydrous or essentially anhydrous, i.e., the amount of water, if any, present therein should be so small as to have no material effect upon the reaction. When the hydrogen halide and/or the Lewis acid contains chlorine, chlorobis(fluorophenyl)methane is formed as a by-product in the reaction. Similarly, when the hydrogen halide and/or the Lewis acid contains bromine, bromobis(fluorophenyl)methane is formed as a by-product in the reaction. Mixtures of chlorobis(fluorophenyl)methane and bromobis(fluorophenyl)methane are formed as by-products when the hydrogen halide and/or the Lewis acid provide both chlorine and bromine to the reaction mixture.
In selecting the Lewis acid for use in the process, consideration should be given to the materials of construction of the facilities used in the process. For example, with plant facilities fabricated from Hastelloy B, it is desirable to avoid use of a Lewis acid in the form of a metal halide having at least two different valence states, such as ferric chloride and ferrous chloride as excessive corrosion may be encountered.
Use of HCl and a Lewis acid chloride salt is preferred from a cost-effectiveness and performance standpoint subject to the above corrosion considerations relative to metal chlorides having different valence states.
By converting the halobis(fluorophenyl)methane into di(fluorophenyl)methanol, corrosion problems that would otherwise occur in many plant facilities during subsequent recovery operations are avoided or at least significantly minimized. Such recovery operations typically involve one or more vessels, distillation columns, or exchangers fabricated from metals such as carbon steel and/or stainless steel. These metals are susceptible to attack by aqueous acids. Because trace amounts of water in the organic phase or residual water in reactors can react with the halobis(fluorophenyl)methane to release hydrogen halide such as HCl or HBr, recovery operations performed in recovery equipment fabricated from carbon steel or stainless steel would be subject to excessive corrosion. Therefore, in the conduct of the above process, this potential problem is avoided or at least greatly minimized by converting the halobis(fluorophenyl)methane into di(fluorophenyl)methanol.
Preferably, 4-fluorobenzaldehyde is recovered from the reaction mass after conducting step C) above. However, in some cases the 4-fluorobenzaldehyde can be used as a reactant while present in the reaction mass after conducting step C). For example, the reaction mass from step C) could be catalytically hydrogenated in order to convert the 4-fluorobenzaldehyde to 4-fluorobenzyl alcohol.
A preferred embodiment of this invention is a process which comprises:
a) heating in a reactor a mixture of fluorobenzene and aluminum chloride with dissolved anhydrous or essentially anhydrous HCl and in an atmosphere of carbon monoxide at a temperature in the range of about 45 to about 100xc2x0 C. and at a total pressure of at least about 150 psig but no higher than the maximum pressure rating of the reactor, to form a reaction mass containing an aluminum chloride complex of 4-fluorobenzaldehyde and at least chlorobis(fluorophenyl)methane by-product;
b) breaking the aluminum chloride complex by quenching the reaction mass with an aluminum chloride-solvating liquid, such as water, to liberate 4-fluorobenzaldehyde;
c) converting chlorobis(fluorophenyl)methane into di(fluorophenyl)methanol; and
d) either (i) recovering 4-fluorobenzaldehyde from the resultant reaction mass, or (ii) using the 4-fluorobenzaldehyde as a reactant without isolation.
In conducting d) of this process it is preferable to recover the 4-fluorobenzaldehyde from the resultant reaction mass.
One procedure which can be effectively utilized in conducting the above preferred embodiment involves the following:
in the conduct of b), a two-phase liquid mixture is formed composed of an aqueous phase and an organic phase comprised of 4-fluorobenzaldehyde together with unreacted fluorobenzene and by-products which include at least chlorobis(fluorophenyl)methane, 2-fluorobenzaldehyde, and 3-fluorobenzaldehyde, said two-phase liquid mixture optionally containing solids comprising hydrated aluminum chloride, and wherein the 4-fluorobenzaldehyde is recovered by separating the phases formed in the conduct of b);
in the conduct of c) chlorobis(fluorophenyl)methane by-product in the separated organic phase is hydrolyzed to di(fluorophenyl)methanol;
in the conduct of d), components that boil at lower temperatures than 4-fluorobenzaldehyde are distilled from the resultant organic phase, and 4-fluorobenzaldehyde is separated by distillation from the less volatile components remaining in the organic phase, said less volatile components comprising at least di(fluorophenyl)methanol.
In a particularly preferred embodiment of this invention, 4-fluorobenzaldehyde is produced by a process which comprises:
a) heating a mixture of fluorobenzene and aluminum chloride in the presence of dissolved anhydrous or essentially anhydrous HCl in an atmosphere of carbon monoxide at a temperature in the range of about 45 to about 90xc2x0 C. and at a total pressure in the range of about 250 psig up to the maximum pressure rating of the reactor being used to form a reaction mass comprising an aluminum chloride complex of 4-fluorobenzaldehyde and chlorobis(fluorophenyl)methane by-product;
b) quenching the reaction mass with water or a dilute aqueous acid such as hydrochloric acid to liberate 4-fluorobenzaldehyde from the aluminum chloride complex and form an organic phase and an aqueous phase free of precipitated aluminum salts;
c) separating the organic phase from the aqueous phase;
d) converting chlorobis(fluorophenyl)methane in the organic phase into di(fluorophenyl)methanol; and
e) optionally, but preferably, recovering 4-fluorobenzaldehyde from the organic phase.
The organic phase formed in b) above will usually comprise 4-fluorobenzaldehyde together with some unreacted fluorobenzene and by-products which include at least chlorobis(fluorophenyl)methane and typically small amounts of 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, and oligomeric materials. The chlorobis(fluorophenyl)methane by-product in this organic phase mixture is hydrolyzed to di(fluorophenyl)methanol, preferably by alkaline hydrolysis, for two main reasons: (1) to minimize corrosion of workup apparatus by HCl that otherwise would have been formed from the hydrolysis of chlorobis(fluorophenyl)methane during an ensuing stripping operation, and (2) to avoid formation of color bodies in the final product.
The magnitude of potential corrosion problem is illustrated by the fact that if the fluorobenzene strip/distillation is conducted without hydrolyzing the chlorobis(fluorophenyl)methane, corrosion rates in excess of 25 mils per year can be experienced with 316L stainless steel in the overhead system. Carbon steel would be expected to have a corrosion rate of at least that magnitude. In contrast, available experimental data indicates that by converting the chlorobis(fluorophenyl)methane to di(fluorophenyl)methanol, the corresponding corrosion rate of the above overhead system should be no more than about 1 mil per year.
In conducting e) above it is preferred to flash or distill from the organic phase components that boil at lower temperatures than 4-fluorobenzaldehyde, including the structural isomers of 4-fluorobenzaldehyde, and to then separate the 4-fluorobenzaldehyde by distillation from the less volatile components in the remaining organic phase such as the di(fluorophenyl)methanol. Alternatively, the 4-fluorobenzaldehyde can be separated as a sidestream during the distillation. To minimize the possibility of emulsion formation during the hydrolysis of the CBFPM in d), it is particularly preferred to wash the separated organic phase from c) with dilute aqueous acid to remove residual aluminum chloride, again separate the phases, and then hydrolyze the chlorobis(fluorophenyl)methane by-product in this separated organic phase to di(fluorophenyl)methanol, followed by distilling from the organic phase components that boil at lower temperatures than 4-fluorobenzaldehyde, and to separate from the remaining organic phase the 4-fluorobenzaldehyde from the less volatile components such as di(fluorophenyl)methanol.
Other embodiments, features and advantages of this invention will become still further apparent from the ensuing description, accompanying drawings, and appended claims.